Abstract
Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion.To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.We show that 1) activation of Src family kinases (SFKs) is common in GBM, 2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic.
Highlights
Malignant glioma tumors are the leading cause of CNS tumor-related mortality
We used western blotting to evaluate the expression of Src, the overall level of Src family of kinases (SFK) activation, and the downstream effector p120 catenin in a panel of GBM xenograft lines
The lethality of human gliomas is associated with tumor cell invasion, which limits the efficacy of surgical and radiological therapies
Summary
Malignant glioma tumors (glioblastoma multiforme or GBM) are the leading cause of CNS tumor-related mortality. Two major factors underlie the poor clinical outcome of these tumors: the intense angiogenic activity of GBM and their aggressive invasion into surrounding normal brain tissue. Studies with the humanized monoclonal antibody bevacizumab (Avastin), which targets the pro-angiogenic factor VEGF, have demonstrated significant therapeutic benefit in patients with recurrent GBM [6,7,8,9]. A randomized phase II trial of bevacizumab versus the bevacizumab/irinotecan combination confirmed the activity of single agent bevacizumab in the recurrent GBM setting [10]. These data have generated significant excitement in the neuro-oncology community, and therapy with bevacizumab is becoming the treatment of choice for recurrent GBM patients. While bevacizumab can result in significant temporary patient benefit, there is an urgent need to understand how antiangiogenic therapies influence basic tumor biology, as well as to develop novel strategies to overcome the pro-invasive effects of bevacizumab therapy
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